Dichloro-alpha,alpha,alpha-trifluorotoluamides

ABSTRACT

DICHLORO-A,A,A-TRIFLUOROTOLUAMIDES ARE PREPARED BY REACTING THE CORRESPONDING ACID CHLORIDE WITH THE DESIRED AMINE IN AN APPROPRIATE SOLVENT. THE RESULTING COMPOUNDS ARE PARTICULARLY USEFUL AS ANTICOCCIDIAL AGENTS AND CENTRAL NERVOUS SYSTEM DEPRESSANTS.

United States Patent Olfice 3,823,134 Patented July 9, 1974 3,823,134 DICHLORO-ugu,a-TRIFLUOROTOLUAMIDES William J. Houlihan, Mountain Lakes, N.J., assignor to Sandoz-Wander, Inc., Hanover, NJ.

No Drawing. Continuation-impart of application Ser. No. 864,869, Oct. 8, 1969, which is a continuation-in-part of application Ser. No. 835,252, June 20, 1969, both now abandoned. This application Dec. 18, 1972, Ser.

Int. Cl. C07c 103/20 US. Cl. 260-239 BA 7 Claims ABSTRACT OF THE DISCLOSURE Dichloro-a,a,a-trifluorotoluamides are prepared by reacting the corresponding acid chloride with the desired amine in an appropriate solvent. The resulting compounds are particularly useful as anticoccidial agents and central nervous system depressants.

where Cl is restricted to either the A or B position; and

when Cl is at A,

Jl-n is at B, and M is an amino radical selected from the group consisting where the substituent groups R and R can be the same or different and are selected from the group comprising hydrogen; straight or branched chain lower alkyl radicals containing 1 to 4 carbon atoms, e.g., methyl, ethyl, etc.; alicyclic radicals containing 5, 6 or 7 ring carbons; straight and branched chain alkenyl or alkynyl radicals concontaining 3 or 4 carbon atoms, e.g., allyl, propargyl or methallyl radicals; and phenyl, tolyl and benzyl radicals;

(ii) heterocyclic radicals having the structure:

wherein X is O, S, or N-R, and R is hydrogen,

a lower alkyl radical containing 1 to 4 carbon atoms, a phenyl radical or where R is lower alkyl containing 1 to 3 carbon atoms; (iii) diamino radicals and substituted diamino radicals of the formula:

R5 NH CH:)..N

where n is 0, 2, 3, or 4; R and R are hydrogen, lower alkyl radical containing 1 to 4 carbon atoms or phenyl radical; (iv) hydroxylamino; (v) ureido; and (vi) 3-azabicyclo[2.2.1]nonyl. Examples of some of the preferred amino structures are as follows:

The diChl0I0-a,cz,a-tIlflIlOlO-tOlUOYl portion of the molecule is derived from acids having the general structure:

0 c1 i i-0H where 1 c1 and JoH have the restriction indicated above for C1 and Jim, and include the following: 2,6-dichloro-m,a,u-trifluoro-m-toluic acid,

E-OH 1 (Ila) 5,6-dichloro-u,u,a-trifluoro-m-toluic acid,

0 EEO-i 1 5,6- dichloro-a,u,a-trifiuoro-o-toluic acid,

The last three acids are synthesized conveniently as a mixture, and the mixture may be used in the process of this invention.

The process for preparing the compounds of this invention is illustrated generally in the following flow diagram:

where J X is a halogen having an atomic weight of about 35 to 80,

M is as defined above, and

Cl is, as previously indicated, restricted to A or B;"

and when Cl is at A, the

0 iL-X and i l-M are at B.

The product I is prepared by treating the acid halide III with an aqueous or an inert solvent solution containing the amine IV. It is preferred that the reaction be allowed to continue for about 2 to 48 hours at temperatures between approximately 15 C. and 75 C.

The preferred acid halide is the acid chloride and the preferred inert solvents are chloroform, ethylene dichloride, benzene, or hexane.

The preferred amines used in the process are ammonia, methylamine, dimethylamine, aniline, cyclohexylamine, N,N-dimethyl hydrazine, phenylhydrazine, N,N,- dimethylamino propylamine, N-propargylbenzylamine, morpholine and 3-azabicyclo[2.2.1]nonane.

The final product I is isolated using conventional techniques such as by concentrating the reaction mixture of 1 step 2 under vacuum, and filtering oif the crude product. The product can be employed in the crude form, or it can be further purified by recrystallizing from 1:1 alcohol-water mixture and thereafter filtering and drying under vacuum.

such as the acetate, succinate, benzoate, p-toluenesulfonate, benzenesulfonate and the like.

This invention also encompasses the acid halide III which is preparedby treating the acid 11 in excess reagent or inert solvent, such as chloroform, ethylene dichloride, benzene, toluene, hexane or heptane with a halogenating agent, e.g. S0Cl PCl P01 and SOBr The reaction is illustrated in the following scheme using thionyl chloride, the preferred halogenation agent:

CF: A sooi A i c1 $011 -----1 l- 31-01 1 I I in (II) (III) It is preferred that the reaction be continued for approximately 1 to 24 hours at a temperature between about 30 C. and C., and preferably at the reflux temperature of the system.

The acids II are prepared by treating in an inert solvent the corresponding lithium intermediate compound of formula V with carbon dioxide:

CF| CF;

0 C01 a L1 01 H0 01 inert solvent where C1 and Li have the aforementioned restrictions for C1 and Y The reaction may be conveniently carried out at a temperature of from about 50 C. to about 10 C. and preferably at a temperature of 25 C. to 10 C. The carbon dioxide used can be a solid or gas. The solvent may be lower hydrocarbons such as pentane, hexane, heptane and the like, ethers such as diethyl ether, dibutyl ether and the like, tetrahydrofuran and benzene.

The process for preparing compound V may be represented by the following reaction:

or. or, I

inert solvent 01 RLl 01 Wm) inert gas in a $1 wherein Cl and Li have the above-stated restriction, and R is straight chain lower alkyl having 1 to 6 carbon atoms. The intermediate lithium compound V may be prepared by reacting a dichloro-trifluorotoluene V1 with a straight chain lower alkyl lithium compound VII having 1 to 6 carbon atoms in a solvent in the presence of an inert gas. The preferred alkyllithium compound is butyl lithium. The solvent may be lower hydrocarbons such as pentane, hexane, heptane, and the like, ethers such as diethyl ether, dibutyl ether, and the like, tetrahydrofuran and benzene. The inert gas may be nitrogen, helium, argon, and the like. The reaction conveniently takes place at temperatures of about ----60 C. to 30 C. with the preferred temperature range being 50 C. to '40 C.

When the starting material of formula VI is 2,4-dichloro-a,a,a-trifluorotoluene,

(VIII) When the starting material of formula V1 is 3,4-dichloroa,a,a-trifluorotoluene,

a mixture is obtained as represented by the structural formula:

Using the two preceding reactions described above, the acids 11a, 11b, He, and 11d can be prepared. When 2,4-di- ChlOIO-oz,ot,a-t1'ifll10l0t0ll16116 VIII is the starting material, the 2,6-diChlO1'O-a,0:,a-tlifll10l'O-D1-t0llli0 acid 11a is obtained. Starting with 3,4-diChr0-a,oz,cc-tl'i.fiu010t0l116l16 X a mixture of the 5,6-dichloro-a,a,a-trifiuoro-m-toluic acid IIb, 5,6-dichloro-m,u,a-trifluoro-o-toluic acid Ho and 4,5- diChlOI'O-a,a,oc-tlifll10IO-O-t0ll1i6 acid -l1d is obtained with the 5,6-dichloro-a,u,a-trifluoro-m-toluic acid IIb predominating. Conventional recovery techniques are utilized for obtaining the acids 11a, 11b, 11c and Hd.

The compounds of formula VI are known and are prepared by methods disclosed in the literature.

The compounds of this invention can be used as herbicides at dosage levels normally employed for this purpose that is, between 2 to 30 lbs. per acre. The preferred range is 2 to 10 lbs. per acre. For this use, the base form of the compound normally is employed.

The instant compounds are also useful in the control of poultry coccidiosis. For this purpose, the base form can be administered in the feedstufl. of the birds; or the salt form, if structurally possible, can be given in the drinking water. If desired, the compounds can be given by direct administration dissolved or suspended in a suitable solvent. In any event, only minor amounts are needed to obtain the desired anticoccidial effect. For optimum results, it is preferred that the base compounds be administered in the feed of the poultry, which is given ad libitum to the birds. Feed concentrations of from 0.005% to 0.3% preferably from 0.01% to 0.1% especially from 0.03% to 0.06% are recommended.

The compounds of formula (I) and the non-toxic acid addition salts which can be formed by some of these compounds as discussed above are also useful because they possess pharmacological activity in animals. (In particular, these compounds are useful as central nervous system depressants, especially as sedative hypnotics and minor tranquillizers as indicated (1) by their ability to produce docility in behavior tests in mice tested according to the 30-word adjective check sheet system basically as described by Irwin, S. (Gordon Research Conference Medicinal Chemistry 1959) and Chem (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins, 1954); (2) by the antagonism of tonic convulsion or death in mice in which convulsive seizures are chemically induced with N-sulfamoylazepine; (3) by the hexobarbital reinduction method of Winter (J. Pharmacol 8: Exp. Therap., 97: 7, 1948) and '(4) by their ability to facilitate the monosynaptic spike obtained by the dorsal-ventral root spinal preparation in male cats.

The compounds of formula I) or the pharmaceutically acceptable acid addition salts which may be formed in certain instances discussed above may be combined with one or more pharmaceutically acceptable carriers or a juvants, and may be administered orally in such forms as tablets, capsules, elixirs, suspensions and the like, parenterally in the form of an injectable solution or suspension or in special forms such as suppositories and the like. Depending upon the compound employed and the mode of administration and exact dosage utilized may vary.

In general, satisfactory results are obtained when these compounds are administered as sedative/hypnotics in the treatment of insomnia/tension at a daily dosage of about 0.4 milligrams to about milligrams per kilogram of animal body weight. This daily dosage is preferably administered 2 to 4 times a day, or in sustained release form. For most large mammals, such as primates, the therapeu tically effective total daily dosage is from about 30 milligrams to about 1000 milligrams. Dosage forms suitable for internal use comprise from about 7.5 milligrams to about 500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

A representative formulation suitable for oral administration 2 to 4 times a day in fertility control is a capsule prepared by standard encapsulating techniques which contain the following:

Ingredients Weight (mg.) 2,6-dichloro-m,a,a-trifluoro-m-toluamide 25 Inert solid diluent (starch, lactose, kaolin) 275 EXAMPLE 1 2,6-dichloro-a,a,a-trifluoro-m-toluic acid g. (0.79 mole) of 2,4-diChl0l0-cz,0:,oc-t1ifll10l'0t0lll6ll6 and 1000 ml. of absolute tetrahydrofuran were charged to a flask equipped with stirrer, dropping funnel, carbon dioxide condenser and gas inlet tube. The system was flushed with dry nitrogen and cooled (carbondioxideacetone bath) to an internal temperature of 50 C. A 660 ml. solution of 15% n-butyllithium (1.06 mole nbutyllithium) in hexane was added dropwise (20 minutes) to the flask. The resulting dark redpurple solution was maintained at -50 C. for about one hour, and then poured onto a slurry of 750 g. powdered carbon dioxide and 250 ml. diethyl ether. After standing for about 20 hours at room temperature, the residue was treated with 750 ml. of 2N sodium hydroxide. The caustic layer was washed with toluene, acidified with concentrated HCl, extracted twice with 200 ml. of methylene chloride and dried with sodium sulfate. The methylene chloride layer 'was filtered and the solvent removed in vacuo. The residue was crystallized from heptane to give 2,'6-diChlO1O-a,a,cttrifluoro-m-toluic acid; m.p. 90-92 C.

EXAMPLE 2 5,6-dichloro-a,a,a-trifluoro-m-toluic acid EFa COOH C1 5,6-dichloro-a,a,a-trifluoro-o-toluic acid COOH 4,5-dichloro-a,u,a-trifluoro-o-toluic acid COOH- 56.5 g. (0.263 mole) of 3,4-dichloro a,a,a-trifluorotoluene and 500 ml. of absolute tetrahydrofuran were charged to a flask equipped with stirrer, dropping funnel, carbon dioxide, condenser and gas inlet tube. The system was flushed with dry nitrogen and cooled (carbon dioxideacetone bath) to an internal temperature of -50 C. A 220 ml. solution of 15% n-butyllithium (0.352 mole) in hexane was added dropwise (20 minutes to the flask). The resulting dark red-purple solution was maintained at 5 0 C. for about one hour, and then poured onto a slurry of 350 g. powdered carbon dioxide and 150 g. diethyl ether. After standing for about 20 hours at room temperature the residue was treated with 300 ml. of 2N sodium hydroxide. The caustic layer was washed with toluene, acidified with concentrated HCl, extracted twice with 200 ml. of methylene chloride and dried with sodium sulfate. The methylene chloride layer was filtered and the solvent removed in vacuo. The residue was crystallized from heptane to give mainly a mixture of 5,6-dichloro-a,a,a-trifiuoro-m-toluic acid, 5,6-diChlOI'O-06,06,0t-l11'lfll101O-O-t01l1l6 acid and 4,5-dichloro-u,a,a-trifiuoro-o-toluic acid.

EXAMPLE 3 2,6dichloro-a,a,u-trifiuoro-m-toluoyl chloride E-Cl 51 A mixture of 140 g. (0.59 mole) of 2,6-d1ChlOr0-oc,oz,atrifiuoro-m-toluic acid and 500 ml. of thionyl chloride was stirred and refluxed for 1.5 hours. The excess thionyl chloride was removed with a water pump and the residue distilled in vacuo to give 2,6-dichloro-a,a,a-trifiuoro-m- 8 EXAMPLE 4 2,6-dichloro-u,a,a-trifluoro-m-toluamide 0 i l-NH:

A solution containing 5.52 g. (0.04 mole) of potassium carbonate, 15 g. (0.12 mole) of 30% ammonium hydroxide, and 150 ml. of distilled water was treated with 11.1 g. (0.04 mole) of the above acid chloride and stirred at room temperature for 16 hours. The solid product was filtered ofi and crystallized from a 1:1 mixture of methanol and water to give 2,6-dichloro-a,a,u-trifluoro-m-toluamide; m.p. 118121 C.

EXAMPLE 5 N,N-dimethyl-2,6-dichloro-a,a,a-trizfluoro-m-toluamide O /CH: LN

A mixture of 13.5 g. (0.12 moles) of 40% dimethylamine in water, 5.52 g. (0.04 mole) of potassium carbonate, and 150 ml. of distilled water was titrated with 11.1 g. (0.04) of the acid chloride of Example 3 and stirred at room temperature for 16 hours. The resultant product was filtered 01f and crystallized from a 1:1 mixture of methanol and water. The product obtained was N,N-dimethyl-2,6-dichloro a,ot,a trifluoro-m-toluamide; m.p.

EXAMPLE 6 2,fi-dichloro-a,u,u-trifluoro-m-toluanilide N ,N -dimethyl-2,6-dichloro-a,a,a-trifluoro-mtoluic acid hydrazide A solution of 11.1 g. (0.04 mole) of the acid chloride of Example 3 in ml. of toluene was added to 6.0 g. (0.10 mole) of N,N-dimethyl hydrazine in ml. of

. toluene. The mixture was stirred at 25 C. for 15 hours.

toluoyl-chloride, b.p. 109-112 at 18 mm.; n 1.5038. 75

The reactants were concentrated in vacuo and the residue crystallized from 1:1 methanol-water. The product was N ,N -dimethyl-2,6-dichloro-a,u,a-tritluoro-m-toluic acid hydrazide; m.p. 158-161 C. i

9 EXAMPLE 3 N'-(3-dimethylaminopropyl)-2,6-dich10ro-a,u,atrifluoro-m-toluamide P: H NCHgCHgCH1N l CH; C1

Using the procedure of the preceding example, 10.2 g. (0.10 mole) of N,N-dimethylaminopropylamine in 150 ml. of toluene was titrated with 11.1 g. (0.10 mole) of the acid chloride of Example 3 in 100 ml. of toluene. The mixture was stirred for hours at 25 C.; and after concentrating by vacuum, the residue was crystallized from 1:1 methanol-water. The product was N-(3-dimethylaminopropyl)-2,6-dichloro 01,41,114 trifiuoro-m-toluamide; m.p. 119-122 C.

EXAMPLE 9 4-(2,6-dichloro-a,a,a-trifluoro-m-toluoyl) morpholine O JLN o A mixture of 10.44 g. (0.12 mole) of morpholine, 5.52 g. (0.04 mole) of potassium carbonate, and 150 ml. of toluenev was titrated with 11.1 g. (0.04 mole) of the acid chloride of Example 3 in 100 ml. toluene and stirred at 25 C. for hours. The reactants, after concentrating in vacuo were recrystallized from 1:1 methanol-water. The product obtained Was 4-(2,6-diChlOrO-a,oz,a-tlifill0l0- m-toluoyl) morpholine; m.p. 106-109 C.

EXAMPLE 10 N -phenyl-2,6-dich1oro-a,a,a-trifluoro-m-toluic acid hydrazide Using the procedure of the preceding example, 8.33 g. (0.03 mole) of the acid chloride of Example 3 was added to 9.72 g. (0.09 mole) of phenylhydrazine in 100 ml. of toluene and stirred for 17 hours at C. The reactants were concentrated in vacuo and recrystallized from 1:1 methanol-water. The product was N -phenyl-2,6-dichloroa,a,a-trifluoro-m-toluic acid hydrazide, m.p. 183"- 186 C.

EXAMPLE 11 N-beuzyl-N-propargyl-2,6-dichloro-a,a,a-trifluoro-mtoluamide 0 CHZCECH 4 8.33 g. (0.03 mole) of the acid chloride of Example 3 was added to 100 ml. of toluene containing 13.1 g. (0.09 mole) of N-propargylbenzylamine. The reactants were 10 mixed for 17 hours at 20 C. After concentrating under vacuum, the product was purified by recrystallizing from 1:1 methanol-water. The product was N-benzyl-N- propargyl-2,6-dichloro-a,a,a-trifluoro-m toluamide; m.p. 122-125 C.

EXAMPLE 12 Using the procedure of the preceding example, 8.33 g. (0.03 mole) of the acid chloride of Example 3 were added to 8.9 g. (0.09 mole) of cyclohexylamine in ml. of toluene. The reactants were stirred at room temperature for about 18 hours and then concentrated on rotary vacuum. The crude product was recrystallized from 1:1 methanol water yielding N-cyclohexyl-2,6-dichloro-a,a,cztrifluoro-m-toluamide; m.p. 206-209 C.

EXAMPLE 13 8.33 g. (0.03 mole) of the acid chloride of Example 3 were added to 11.25 g. (0.09 mole) of 3-azabicyc1o[2.2.1] nonane in ml. of toluene. The reactants were stirred for 18 hours at 25 C. and then concentrated under vacuum. The residue was recrystallized using 1:1 methanolwater. The product obtained was N-(2,6-diCh10l'O-a,(x,0t-t1'ifluoro-m-toluoyl)-3-azabicyclo[2.2.1]nonane; m.p. 187- When the process of this example is carried out and methylamine, allylamine, o-toluidine, piperazine, N-

methylpiperazine, N-phenylpiperazine, piperazine-l-carboxylic acid ethyl ester, thiomorpholine, hydroxylamine or urea is substituted for What is claimed is:

1. The compound which is N ,N -dimethyl-2,6-dichloro-a,a,a-trifluoro-m-toluic acid hydrazide.

2. The compound which is N-(3-dimethylaminopropyl) 2,6 dichloro-a,a,a-trifluoro-m-toluamide.

3. The compound which is 4-(2,6dichloro-a,,m-trifluoro-m-toluoyl)morpholine.

4. The compound which is N -phenyl-2,6-dichloroa,a,a-trifluoro-m-toluic acid hydrazide.

11 5. The compound which is N-benzyl-N-propargyl-2,6- dichloro-a,u,u-trifluoro-m-toluamide.

6. The compound which is N-cyclohexyl-2,6-dichloroa,a,a-trifluoro-m-toluamide.

7. The compound which is N-(2,6-dichloro-a,a,a-trifluoro-m-toluoyl) 3-azabicyclo[2.2.1]nonane.

References Cited UNITED STATES PATENTS 3,357,876 12/1967 Baker et a1. 260-558 3,436,208 4/1969 Lemin 260--558 12 3,531,277 9/1970- Lemin 260558 3,530,181 9/1970 Soloway et a1. 260558 3,253,900 5/ 1966 Newcomer et a1. 260-558 HARRY I. MOATZ, Primary Examiner Us. 01. X.R.

260243 B, 247.7 H, 268 C, 500.5, 553 E, 558 H, 558 D; 424244, 246, 248, 250, 315, 322, 324 

